Cold exposure remodels mitochondria in muscle and fat

The pace of science in examining the power of cold exposure, even mild cold exposure, is remarkable. A new study has driven this to the intracellular level. In short, want to get lean? Get cold first.

There are two well-described thermogenic sites; brown adipose tissue (BAT) and skeletal muscle, which utilize distinct mechanisms of heat production. In BAT, mitochondrial metabolism is the molecular basis of heat generation, while it serves only a minor role in supplying energy for thermogenesis in muscle. Here, we wanted to document changes in mitochondrial ultrastructure in these two tissue types upon adaptation to mild (16°C) and severe (4°C) cold in mice. When reared at thermoneutrality (29°C), mitochondria in both tissues were loosely packed with irregular cristae. Interestingly, adaptation to even mild cold initiated ultrastructural remodeling of mitochondria including acquisition of more elaborate cristae structure in both thermogenic sites. The shape of mitochondria in the BAT remained mostly circular, whereas the intermyofibrilar mitochondria in the skeletal muscle became more elongated and tubular. The most dramatic remodeling of mitochondrial architecture was observed upon adaptation to severe cold. In addition, we report cold-induced alteration in levels of humoral factors: FGF21, IL1α, PYY, TNFα, and IL6 were all induced whereas both insulin and leptin were downregulated. In summary, adaptation to cold leads to enhanced cristae formation in mitochondria in the skeletal muscle and BAT. Further, this study indicates that circulating cytokines might play an important role in the synergistic recruitment of the thermogenic program including crosstalk between muscle and BAT for turning either of them on or off, depending on thermogenic demand. We propose that cytokines are utilized to mediate synergistic recruitment of BAT and muscle and their signaling might have an evolutionary importance in the development of endothermy among eutherian mammals.

Data presented here suggest that mitochondrial architecture at both thermogenic sites is closely associated with the degree of cold exposure. In addition to shivering, skeletal muscle metabolism also plays a key role in nonshivering thermogenesis . The mechanism activation of NST in the skeletal muscle needs more precise understanding. Our data suggest that cytokines, especially FGF21, might be a potential determinant of relative recruitment of BAT and skeletal muscle. A better understanding of how NST mechanisms in skeletal muscle operate and are turned on and off may provide pharmacological targets to increase whole body energy expenditure to counter metabolic diseases such as obesity and type II diabetes. Towards this understanding, a few key questions that should be addressed by future studies, including: identifying molecular regulators of mitochondrial cristae formation in BAT and skeletal muscles; delineating the signaling mechanism that links the energy demand of the body with mitochondrial cristae enrichment; identifying the role of adipokines/myokines in energy sensing and their subsequent recruitment during high-energy demanding conditions like cold and exercise; describing the muscle activity dependent secretion of myokines in coordination of energy homeostasis; and understanding the role of cytokines in mitochondrial architecture in thermogenic organs.